Molecular and Cellular Biochemistry

, Volume 416, Issue 1–2, pp 11–22 | Cite as

Mitochondrial defects associated with β-alanine toxicity: relevance to hyper-beta-alaninemia

  • Aza Shetewy
  • Kayoko Shimada-Takaura
  • Danielle Warner
  • Chian Ju Jong
  • Abu-Bakr Al Mehdi
  • Mikhail Alexeyev
  • Kyoko Takahashi
  • Stephen W. SchafferEmail author


Hyper-beta-alaninemia is a rare metabolic condition that results in elevated plasma and urinary β-alanine levels and is characterized by neurotoxicity, hypotonia, and respiratory distress. It has been proposed that at least some of the symptoms are caused by oxidative stress; however, only limited information is available on the mechanism of reactive oxygen species generation. The present study examines the hypothesis that β-alanine reduces cellular levels of taurine, which are required for normal respiratory chain function; cellular taurine depletion is known to reduce respiratory function and elevate mitochondrial superoxide generation. To test the taurine hypothesis, isolated neonatal rat cardiomyocytes and mouse embryonic fibroblasts were incubated with medium lacking or containing β-alanine. β-alanine treatment led to mitochondrial superoxide accumulation in conjunction with a decrease in oxygen consumption. The defect in β-alanine-mediated respiratory function was detected in permeabilized cells exposed to glutamate/malate but not in cells utilizing succinate, suggesting that β-alanine leads to impaired complex I activity. Taurine treatment limited mitochondrial superoxide generation, supporting a role for taurine in maintaining complex I activity. Also affected by taurine is mitochondrial morphology, as β-alanine-treated fibroblasts undergo fragmentation, a sign of unhealthy mitochondria that is reversed by taurine treatment. If left unaltered, β-alanine-treated fibroblasts also undergo mitochondrial apoptosis, as evidenced by activation of caspases 3 and 9 and the initiation of the mitochondrial permeability transition. Together, these data show that β-alanine mediates changes that reduce ATP generation and enhance oxidative stress, factors that contribute to heart failure.


Electron transport chain Oxidative stress Respiration Taurine Mitochondrial fragmentation Apoptosis 



We appreciate the financial support of Taisho Pharmaceutical Co. and the intellectual input of our deceased colleague, Dr. Junichi Azuma, Osaka, Japan.


  1. 1.
    Wu FS, Gibbs TT, Farb DH (1993) Dual activation of GABAA and glycine receptors by beta-alanine inverse modulation by progesterone and 5 alpha-pregnan-3 alpha-ol-20-one. Eur J Pharmacol 246:239–246CrossRefPubMedGoogle Scholar
  2. 2.
    Tiedje KE, Stevens K, Barnes S, Weaver DF (2010) β-alanine as a small molecule neurotransmitter. Neurochem Int 57:177–188CrossRefPubMedGoogle Scholar
  3. 3.
    Hayaishi O, Nishizuka Y, Tatibana M, Takeshita M, Kuno S (1961) Enzymatic studies on the metabolism of β-alanine. J Biol Chem 236:781–790PubMedGoogle Scholar
  4. 4.
    Derave W, Everaert I, Beeckman S, Baguet A (2010) Muscle carnosine metabolism and β-alanine supplementation in relation to exercise and training. Sports Med 40:247–263CrossRefPubMedGoogle Scholar
  5. 5.
    Yamada EW, Jakoby WB (1960) Aldehyde oxidation. V. Direct conversion of malonic semialdehyde to acetyl-coenzyme A. J Biol Chem 235:589–594PubMedGoogle Scholar
  6. 6.
    Gibson MK, Jakobs C (2001) Disorder of β- and γ-amino acids in free and peptide-linked forms. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease. McGraw Hill, New York, pp 2079–2105Google Scholar
  7. 7.
    Slavik M, Blanc O, Smith KJ, Slavik J (1983) 6-azauridine triacetate induced hyper beta-alaninemia and its decrease by administration of pyridoxine. J Nutr Sci Vitaminol (Tokyo) 29:631–635CrossRefPubMedGoogle Scholar
  8. 8.
    Kurozumi Y, Abe T, Yao WB, Ubuka T (1999) Experimental beta-alaninuria induced by (aminooxy)acetate. Acta Med Okayama 53:13–18PubMedGoogle Scholar
  9. 9.
    Gemelli T, de Andrade RB, Rojas DB, Bonorino NF, Mazzola PN, Tortorelli LS, Filho CSD, Wannmacher CMD (2013) Mol Cell Biochem 380:161–170CrossRefPubMedGoogle Scholar
  10. 10.
    Schaffer SW, Shimada-Takaura K, Jong CJ, Ito T, Takahashi K (2016) Impaired energy metabolism of the taurine-deficient heart. Amino Acids 7:1–10Google Scholar
  11. 11.
    Grishko V, Pastukh V, Solodushko V, Gillespie M, Azuma J, Schaffer S (2003) Apoptotic cascade initiated by angiotensin II in neonatal cardiomyocytes: role of DNA damage. Am J Physiol 285:H2364–H2372Google Scholar
  12. 12.
    Kussmaul L, Hirst J (2006) The mechanism of superoxide production by NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria. Proc Natl Acad Sci USA 103(20):7607–7612CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Muller FL, Liu Y, van Remmen H (2004) Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 279(47):49064–49073CrossRefPubMedGoogle Scholar
  14. 14.
    Ahmad T, Aggarwal K, Pattnaik B, Mukherjee S, Sethi T, Tiwari BK, Kumar M, Micheal A, Mabalirajan U, Ghosh B, Roy SS, Aggarwal A (2013) Computational classification of mitochondrial shapes reflects stress and redox state. Cell Death Dis 4:1–10CrossRefGoogle Scholar
  15. 15.
    Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators fis1, drp1 and opa1 in apoptosis. Mol Biol Cell 15:5001–5011CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Caruso J, Charles J, Unruh K, Giebel R, Learmonth L, Potter W (2012) Ergogenic effects of β-alanine and carnosine: proposed future research to quantify their efficacy. Nutrients 4:586–601CrossRefGoogle Scholar
  17. 17.
    Jong CJ, Ito T, Mozaffari M, Azuma J, Schaffer S (2010) Effects of β-alanine treatment on mitochondrial taurine level and 5-taurinomethyluridine content. J Biomed Sci 17(S1):525–532Google Scholar
  18. 18.
    Jong CJ, Azuma J, Schaffer S (2012) Mechanism underlying the antioxidant activity of taurine: prevention of mitochondrial oxidant production. Amino Acids 42(6):2223–2232CrossRefPubMedGoogle Scholar
  19. 19.
    Schaffer SW, Jong CJ, Ito T, Azuma J (2014) Role of taurine in the pathologies of MELAS and MERRF. Amino Acids 46(1):47–56CrossRefPubMedGoogle Scholar
  20. 20.
    Kirino Y, Goto Y, Campos Y, Arenas J, Suzuki T (2005) Specific correlation between the wobble modification deficiency in mutant tRNAs and the clinical features of a human mitochondrial disease. Proc Natl Acad Sci USA 102:7127–7132CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Turrens J, Boveris A (1980) Generation of superoxide anion by the NADH dehydrogenase of bovine heart mitochondria. Biochem J 191:421–427CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wu CC, Bratton SB (2013) Regulation of the intrinsic apoptosis pathway by reactive oxygen species. Antioxid Redox Signal 19(6):546–558CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11(9):621–632CrossRefPubMedGoogle Scholar
  24. 24.
    D’Alessio M, De Nicola M, Coppola S, Gualandi G, Pugliese L, Cerella C, Cristofanon S, Civtareale P, Ciriolo MR, Bergamaschi A, Magrini A, Ghibelli L (2005) Oxidative Bax dimerization promotes its translocation to mitochondria independently of apoptosis. FASEB J 19:1504–1506PubMedGoogle Scholar
  25. 25.
    Matsuzawa A, Ichijo H (2008) Redox control of cell fate by MAP kinase: physiological roles of ASK1-MAP kinase pathway in stress signaling. Biochim Biophys Acta 1780(11):1325–1336CrossRefPubMedGoogle Scholar
  26. 26.
    Leboucher GP, Tsai YC, Yang M, Shaw KC, Zhou M, Veenstra TD, Glickman MH, Weissman AM (2012) Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptoSsis. Mol Cell 47(4):547–557CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Schaffer S, Solodushko V, Pastukh V, Ricci C, Azuma J (2003) Possible cause of taurine deficient cardiomyopathy: potentiation of angiotensin II action. J Cardiovasc Pharmacol 41(5):751–759CrossRefPubMedGoogle Scholar
  28. 28.
    Ramila KC, Jong CJ, Pastukh V, Ito T, Azuma J, Schaffer SW (2015) Role of protein phosphorylation in excitation-contraction coupling in taurine deficient hearts. Am J Physiol 308(3):H232–H239Google Scholar
  29. 29.
    Doenst T, Nguyen TD, Abel ED (2013) Heart failure compendium: cardiac metabolism and heart failure: implications beyond ATP production. Circ Res 113:709–724CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Aza Shetewy
    • 1
  • Kayoko Shimada-Takaura
    • 1
  • Danielle Warner
    • 1
  • Chian Ju Jong
    • 1
  • Abu-Bakr Al Mehdi
    • 1
  • Mikhail Alexeyev
    • 2
  • Kyoko Takahashi
    • 3
  • Stephen W. Schaffer
    • 1
    Email author
  1. 1.Department of PharmacologyUniversity of South Alabama College of MedicineMobileUSA
  2. 2.Department of Cell Biology/NeuroscienceUniversity of South Alabama College of MedicineMobileUSA
  3. 3.Graduate School of Pharmaceutical SciencesOsaka UniversityOsakaJapan

Personalised recommendations